EP1476434B1 - Pyridazine derivatives, use of the same as medicaments, pharmaceutical compositions and method for producing the same - Google Patents

Abstract

The invention relates to a pyridazine derivative of formula (I), wherein the variables are as defined herein, pharmaceutical composition thereof, process for its preparation, and its pharmaceutical use.

Description

The invention relates to novel pyridazine derivatives, their preparation, their use as medicaments, in particular as inhibitors of cathepsin K., as well as pharmaceutical compositions containing them.

Metabolic enzymes such as proteases or kinases are widely distributed enzymes in the animal kingdom. By way of non-exhaustive examples, mention may be made, as bibliographic references for proteases, of the documents: "Methods in Enzymology XLII (1975)" and "Journal of Medicinal Chemistry" vol. 43 No. 3 (Leung, G., Abbenante and D.P. Fairlie) and for kinases, "Methods in Enzymology", Vol 80 (1981) (Academic Press Inc.).

Among the proteases capable of selectively catalyzing the hydrolysis of polypeptide linkages, there may be mentioned four main classes: aspartic protease, serine, cysteine and metalloprotease.

Aspartic protease that may be mentioned in particular HIV-1 protease, renin, plasmepsins, cathepsin D.

As serine protease, mention may in particular be made of thrombin, factor Xa, elastase, tryptase, the "complement of convertases", the NS3 protease of hepatitis C.

Among the cysteine proteases, there are three structurally distinct groups, the papain group and cathepsins, the ICE group (caspases) and the picorna-viral group (similar to serine proteases in which serine is replaced by cysteine).

Thus, there may be mentioned in particular cathepsin K, cathepsin B, cathepsin L, cathepsin S, caspases, rhinovirus 3C protease and papaines and calpaines.

As metalloprotease, mention may in particular be made of angiotensin converting enzyme, neutral endopeptidase and the mixture of the two, matrix metalloprotease as well as Tumor-necrosis Factor-α-Converting Enzyme.

These kinase or protease enzymes are involved in processes of catabolization and inter and intracellular communication: they play an important role in a large number of diseases of different domains such as in particular the cardiovascular field, oncology, the central nervous system, inflammation, osteoporosis and also infectious, parasitic, fungal or viral diseases. This is why these proteins are targets of great interest for pharmaceutical research.

The patent application EP 0 621 270 describes pyridazine derivatives of type IV collagenase inhibitors, useful in particular against cancer metastasis.

dans laquelle :

• R₁ représente un atome d'hydrogène ou un groupement alkyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone, COR, COOR, R étant choisi dans le groupe constitué par un radical alkyle linéaire ou ramifié renfermant de 1 à 6 atomes de carbone, éventuellement substitué par un radical pyridyle ou carbamoyle, un radical -CH₂-alkényle linéaire ou ramifié renfermant au total de 3 à 9 atomes de carbone, aryle renfermant de 6 à 10 atomes de carbone ou aralkyle renfermant de 7 à 11 atomes de carbone, le noyau du radical aryle ou aralkyle étant éventuellement substitué par un radical OH, NH₂, NO₂, alkyle linéaire ou ramifié renfermant de 1 à 6 atomes de carbone, alkoxy linéaire ou ramifié renfermant de 1 à 6 atomes de carbone ou par 1 à 3 atomes d'halogène,
• R₂ représente un groupement répondant à la formule (II) suivante :
  
  dans laquelle :
  • n vaut 0,1,2 ou 3 ; une double liaison pouvant éventuellement être présente lorsque n vaut 2 ou 3;
  • X est l'un des groupements:
    • groupement hétérocyle monocyclique ou bicyclique saturé ou insaturé; ou
    • un groupement aryle renfermant de 6 à 10 atomes de carbone ou aralkyle renfermant de 7 à 11 atomes de carbone, le noyau du radical aryle ou aralkyle étant éventuellement substitué par un radical OH, NH₂, NO₂, alkyle linéaire ou ramifié renfermant de 1 à 6 atomes de carbone, alkoxy linéaire ou ramifié renfermant de 1 à 6 atomes de carbone ou par 1 à 3 atomes d'halogène ; ou
    • un groupement NR₄R₅, R₄ étant un groupement alkyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone ou un groupement COR, CONHR, CSNHR ou SO₂R, R ayant la signification donnée précédemment et R₅ étant un atome d'hydrogène ou un radical alkyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone ; ou
    • un groupement COR, R ayant la signification donnée précédemment et R₅ étant un atome d'hydrogène ou un radical alkyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone ; ou
• R₃ est un groupement de formule -Y-(CH₂)_m-C(CN)R₆R₇ , dans laquelle :
  • Y est un atome d'oxygène ou un groupement -N(R₈)-,
  • R₈ étant un atome d'hydrogène ou un groupement alkyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone,
  • m vaut 0,1,2 ou 3,
  • R₆ est un atome d'hydrogène, un groupement alkyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone ou un groupement aryle ou alkaryle, le noyau du radical aryle ou aralkyle étant éventuellement substitué par un radical OH, NH₂, NO₂, alkyle linéaire ou ramifié renfermant de 1 à 6 atomes de carbone, alkoxy linéaire ou ramifié renfermant de 1 à 6 atomes de carbone, aryloxy renfermant de 7 à 11 atomes de carbone, ce groupement aryloxy étant lui-même éventuellement substitué par 1 à 3 halogènes,
  • R₇ est un atome d'hydrogène ou un groupement alkyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone,
  • ou R₆ et R₇ pouvant former ensemble un cycle saturé à 6 chaînons ;
  lesdits produits de formule (I) étant sous toutes les formes isomères possibles, racémiques, énantiomères et diastéréo-isomères ;
  ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques de ces produits.

The subject of the present invention is thus the products of formula (I):

in which :

• R ₁ represents a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atoms, COR, COOR, R being chosen from the group consisting of a linear or branched alkyl radical containing from 1 to 6 carbon atoms optionally substituted by a pyridyl or carbamoyl radical, a linear or branched -CH ₂ -alkenyl radical containing in total from 3 to 9 carbon atoms, aryl containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms the ring of the aryl or aralkyl radical being optionally substituted with an OH, NH ₂ , NO ₂ radical, linear or branched alkyl containing from 1 to 6 carbon atoms, linear or branched alkoxy containing from 1 to 6 carbon atoms or by 1 at 3 halogen atoms,
• R ₂ represents a group corresponding to the following formula (II):
  
  in which :
  • n is 0,1,2 or 3; a double bond possibly being present when n is 2 or 3;
  • X is one of the groupings:
    • saturated or unsaturated monocyclic or bicyclic heterocyclic group; or
    • an aryl group containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms, the ring of the aryl or aralkyl radical being optionally substituted by an OH, NH ₂ , NO ₂ radical, linear or branched alkyl containing from 1 to with 6 carbon atoms, linear or branched alkoxy containing 1 to 6 carbon atoms or 1 to 3 halogen atoms; or
    • a group NR ₄ R ₅ , R ₄ being a linear or branched alkyl group having from 1 to 6 carbon atoms or a group COR, CONHR, CSNHR or SO ₂ R, R having the meaning given above and R ₅ being a hydrogen atom; hydrogen or a linear or branched alkyl radical having 1 to 6 carbon atoms; or
    • a COR group, R having the meaning given above and R ₅ being a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; or
• R ₃ is a group of formula -Y- (CH ₂ ) _m -C (CN) R ₆ R ₇ , in which:
  • Y is an oxygen atom or a group -N (R ₈ ) -,
  • R ₈ being a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atoms,
  • m is 0,1,2 or 3,
  • R ₆ is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms or an aryl or alkaryl group, the ring of the aryl or aralkyl radical being optionally substituted with an OH, NH ₂ , NO ₂ radical; , linear or branched alkyl containing from 1 to 6 atoms of carbon, linear or branched alkoxy containing from 1 to 6 carbon atoms, aryloxy containing from 7 to 11 carbon atoms, this aryloxy group being itself optionally substituted by 1 to 3 halogens,
  • R ₇ is a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atoms,
  • or R ₆ and R ₇ may together form a saturated 6-membered ring;
  said products of formula (I) being in all possible isomeric, racemic, enantiomeric and diastereoisomeric forms;
  as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of these products.

The products of the present invention as defined above and below have properties inhibiting metabolic enzymes as defined above including kinases or proteases such as cysteine proteases or serine proteases.

The products of the present invention can thus notably be useful in the prevention or treatment of diseases in which such metabolic enzymes are involved, such as certain cardiovascular diseases, diseases of the central nervous system, inflammatory diseases, bone diseases such as, for example osteoporosis, infectious diseases requiring, in particular for their therapy, anti-infectives or certain cancers.

• le terme aryle renfermant de 6 à 10 atomes de carbone désigne un radical insaturé, comportant un ou deux cycles fusionnés, éventuellement interrompu par un à trois hétéroatomes choisis parmi azote, oxygène et soufre. On peut citer: phényle, naphtyle.
• le terme aralkyle renfermant de 7 à 11 atomes de carbone désigne un radical aryle tel que ci-dessus, lié par un radical alkyle linéaire ou ramifié, ce radical alkyl ayant de 1 à 5 atomes de carbone. On peut citer notamment le benzyle.
• le terme aralkyloxy indique la présence d'un oxygène terminal sur le groupe aralkyle précité.
• le terme radical hétérocyclique monocyclique désigne un radical saturé ou insaturé constitué de 5 ou 6 chaînons tel que l'un ou plusieurs des chaînons représente un atome d'oxygène, de soufre ou d'azote : un tel radical hétérocyclique désigne ainsi un radical carbocyclique interrompu par un ou plusieurs hétéroatomes choisis parmi les atomes d'oxygène, d'azote ou de soufre étant entendu que les radicaux hétérocycliques peuvent renfermer un ou plusieurs hétéroatomes choisis parmi les atomes d'oxygène, d'azote ou de soufre et que lorsque ces radicaux hétérocycliques comportent plus d'un hétéroatome, les hétéroatomes de ces radicaux hétérocycliques peuvent être identiques ou différents. On peut citer notamment le radical dioxolane, dioxane, dithiolane, thiooxolane, thiooxane, morpholinyle, pipérazinyle, pipérazinyle substitué par un radical alkyle, linéaire ou ramifié, renfermant au plus 4 atomes de carbone, pipéridyle, thiényle tel que 2-thiényle et 3-thiényle, furyle tel que 2 furyle, pyrimidinyle, pyridyle tel que 2-pyridyle, 3-pyridyle et 4-pyridyle pyrimidyle, pyrrolyle, thiazolyle, isothiazolyle, diazolyle, thiadiazolyle, triazolyle, tétrazolyle libre ou salifié thiadiazolyle, thiatriazolyle, oxazolyle, oxadiazolyle, 3- ou 4-isoxazolyle. On peut citer tout particulièrement les radicaux morpholinyle, thiényle tel que 2-thiényle et 3-thiényle, furyle tel que 2-furyle , tétrahydrofuryle, thiényle, tétrahydrothienyle, pyrrolyle, pyrrolinyle, pyridyle et pyrrolidinyle.
• le terme radical hétérocyclique bicyclique désigne un radical saturé ou insaturé constitué de 8 à 12 chaînons tel que l'un ou plusieurs des chaînons représente un atome d'oxygène, de soufre ou d'azote et notamment des groupes hétérocycliques condensés contenant au moins un hétéroatome choisi parmi le soufre, l'azote et l'oxygène, par exemple benzothiényle tel que 3-benzothiényle, benzothiazolyle, quinolyle, tetralone, benzofuryle, benzopyrrolyle, benzimidazolyle, benzoxazolyle, thionaphtyle, indolyle ou purinyle.

In the products of formula (I) and in the following:

• the term aryl containing from 6 to 10 carbon atoms denotes an unsaturated radical containing one or two fused rings, optionally interrupted by one to three heteroatoms chosen from nitrogen, oxygen and sulfur. There may be mentioned: phenyl, naphthyl.
• the term aralkyl containing from 7 to 11 carbon atoms denotes an aryl radical such as above, linked by a linear or branched alkyl radical, this alkyl radical having from 1 to 5 carbon atoms. In particular, mention may be made of benzyl.
• the term aralkyloxy indicates the presence of a terminal oxygen on the aforementioned aralkyl group.
• the term monocyclic heterocyclic radical denotes a saturated or unsaturated radical consisting of 5- or 6-membered rings such that one or more of the chain members represents an oxygen, sulfur or nitrogen atom: such a heterocyclic radical thus denotes an interrupted carbocyclic radical; by one or more heteroatoms chosen from oxygen, nitrogen or sulfur atoms, it being understood that the heterocyclic radicals may contain one or more heteroatoms chosen from oxygen, nitrogen or sulfur atoms and that when these radicals heterocyclics contain more than one heteroatom, the heteroatoms of these heterocyclic radicals may be the same or different. Mention may in particular be made of the dioxolane, dioxane, dithiolane, thiooxolane, thiooxane, morpholinyl, piperazinyl, piperazinyl radical substituted by a linear or branched alkyl radical, containing at most 4 carbon atoms, piperidyl, thienyl such as 2-thienyl and 3- thienyl, furyl such as 2-furyl, pyrimidinyl, pyridyl such as 2-pyridyl, 3-pyridyl and 4-pyridyl pyrimidyl, pyrrolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, triazolyl, free or salted tetrazolyl thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, 3- or 4-isoxazolyl. Mention may in particular be made of morpholinyl and thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, tetrahydrofuryl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyridyl and pyrrolidinyl.
• the term bicyclic heterocyclic radical denotes a saturated or unsaturated radical consisting of 8 to 12 members such that one or more of the chain members represents an oxygen, sulfur or nitrogen atom and in particular fused heterocyclic groups containing at least one heteroatom selected from sulfur, nitrogen and oxygen, for example benzothienyl such as 3-benzothienyl, benzothiazolyl, quinolyl, tetralone, benzofuryl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl or purinyl.

• parmi les composés de salification, des bases minérales telles que, par exemple, un équivalent de sodium, de potas-sium, de lithium, de calcium, de magnésium ou d'ammonium ou des bases organiques telles que, par exemple, la méthylamine, la propylamine, la triméthylamine, la diéthylamine, la tri- éthylamine, la N,N-diméthyléthanolamine, le tris (hydroxy-méthyl)amino méthane, l'éthanolamine, la pyridine, la pico-line, la dicyclohexylamine, la morpholine, la benzylamine, la procaïne, la lysine, l'arginine, l'histidine, la N-méthyl- glucamine,
• Les sels d'addition avec les acides minéraux ou organiques des produits de formule (1) peuvent être, par exemple, les sels formés avec les acides chlorhydrique, bromhydrique, iodhydrique, nitrique, sulfurique, phosphorique, propionique, acétique, trifluoroacétique, formique, benzoïque, maléique, fumarique, succinique, tartrique, citrique, oxalique, glyoxylique, aspartique, ascorbique, les acides alcoylmonosulfoniques tels que par exemple l'acide méthanesulfonique, l'acide éthanesulfonique, l'acide propanesulfonique, les acides alcoyldisulfoniques tels que par exemple l'acide méthanedisulfonique, l'acide alpha, bêta-éthanedisulfonique, les acides arylmonosulfoniques tels que l'acide benzènesulfonique et les acides aryldisulfoniques.

The compounds of formula (1) may be salified by the various groups known to those skilled in the art, among which may be mentioned, for example:

• among the salification compounds, mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxy-methyl) amino methane, ethanolamine, pyridine, pico-line, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine,
• The addition salts with the inorganic or organic acids of the products of formula (1) may be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and aryldisulphonic acids.

It may be recalled that the stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position, and the different possible rotational conformations of the ethane derivatives. However, there is another type of stereoisomerism, due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, often called geometric isomerism or cis-trans isomerism. The term stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.

The subject of the present invention is in particular the products of formula (I) as defined above in which R ₁ is a hydrogen atom, a methyl, benzyl, -COO-benzyl or -CO-methylene-benzyl group, in particular those in which n is 0 or 2.

Preferably, R ₅ is a hydrogen atom.

Also of interest are the products of formula (I) in which X is a phenyl, -NHCO-benzyl group or those in which X is the grouping.

Preferably, R ₆ , R ₇ and / or R ₈ are, independently of one another, a hydrogen atom.

R ₆ may advantageously be the phenyl group, -C ₆ H ₄ -OC ₆ H ₅ or -C ₂ H ₄ -OC ₆ H ₄ Br.

Also of interest are the products of formula (I) in which m is 0 or 2.

The present invention also particularly relates to certain products of formula (I).

Process according to the invention

dans laquelle R₁ et R₂ ont la même signification que ci-dessus,
avec un amino-nitrile ou cyano-hydrine de formule HR₃, dans laquelle R₃ a la même signification que ci-dessus, pour obtenir un produit de formule (I).The present invention thus also relates to a process for the preparation of the products of formula (I), as defined above, characterized in that it comprises the reaction step of a product of formula (IV)

in which R ₁ and R ₂ have the same meaning as above,
with an amino-nitrile or cyano-hydrin of formula HR ₃ , wherein R ₃ has the same meaning as above, to obtain a product of formula (I).

1. 1) une étape au cours de laquelle on fait réagir un produit de formule (II)
   
   avec un chlorure d'acide de formule R₂Cl, dans laquelle R₁ et R₂ ont les mêmes significations que ci-dessus et R' est un groupement alkyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone, pour obtenir le produit de formule (III);
   
2. 2) une étape au cours de laquelle on hydrolyse le produit de formule (III) obtenu à l'étape 1) en le produit de formule (IV);
   
3. 3) une étape au cours de laquelle on fait réagir le produit de formule (IV) obtenu à l'étape 2) avec un amino-nitrile ou cyano-hydrine de formule HR₃, dans laquelle R₃ a la même signification que ci-dessus, pour obtenir un produit de formule (I).

The present invention thus also relates to a process for the preparation of the products of formula (I), as defined above, characterized in that it comprises:

1. 1) a step during which a product of formula (II) is reacted
   
   with an acid chloride of formula R ₂ Cl, in which R ₁ and R ₂ have the same meanings as above and R 'is a linear or branched alkyl group having 1 to 6 carbon atoms, to obtain the product of formula (III);
   
2. 2) a step during which the product of formula (III) obtained in step 1) is hydrolyzed to the product of formula (IV);
   
3. 3) a step in which the product of formula (IV) obtained in step 2) is reacted with an amino-nitrile or cyano-hydrin of formula HR ₃ , in which R ₃ has the same meaning as above; above, to obtain a product of formula (I).

The first process described has as a starting material a pyridazine carboxylic acid of formula (IV) which is reacted directly with a suitable nitrile derivative.

The second method is based on the preparation of an intermediate ester.

• l'étape 1) permet d'obtenir le produit de formule (III)
  
  à partir du produit de formule (II) ;
• l'étape 2), qui est un étape connue en soi d'hydrolyse d'un ester et a lieu généralement en présence d'une base, permet d'obtenir le produit de formule (IV)
  
  à partir du produit de départ de formule (III) ;
• l'étape 3) permet d'obtenir le produit de formule (I) à partir du produit de formule (IV).
  Quant aux étapes optionnelles, elles sont d'une manière générale des réactions classiques, bien connues de l'homme du métier.
  Ainsi, les fonctions réactives qu'il convient, le cas échéant, de protéger sont généralement les fonctions acides carboxyliques, amines, amides et hydroxy.
  La protection de la fonction acide est notamment effectuée sous forme d'esters d'alkyle, d'esters allyliques; de benzyle, benzhydryle ou p-nitrobenzyle.
  La déprotection est effectuée par saponification, hydrolyse acide, hydrogénolyse, ou encore clivage à l'aide de complexes solubles du Palladium O.
  La protection des amines et amides est notamment effectuée sous forme de dérivés benzylés, sous forme de carbamates, notamment d'allyle, benzyle, phényle ou tertbutyle, ou encore sous forme de dérivés silylés tels que les dérivés tertbutyle diméthyl, triméthyl, triphényl

ou encore diphényl tertbutyl-silyle.Such a process is therefore essentially composed of the following 3 steps:

• step 1) makes it possible to obtain the product of formula (III)
  
  from the product of formula (II);
• step 2), which is a step known per se of hydrolysis of an ester and takes place generally in the presence of a base, makes it possible to obtain the product of formula (IV)
  
  from the starting material of formula (III);
• step 3) makes it possible to obtain the product of formula (I) from the product of formula (IV).
  As for the optional steps, they are generally conventional reactions, well known to those skilled in the art.
  Thus, the reactive functions that should be protected, if necessary, are generally the carboxylic acid, amine, amide and hydroxy functional groups.
  The protection of the acid function is in particular carried out in the form of alkyl esters, allyl esters; benzyl, benzhydryl or p-nitrobenzyl.
  Deprotection is carried out by saponification, acid hydrolysis, hydrogenolysis, or cleavage using soluble complexes of Palladium O.
  The protection of the amines and amides is in particular carried out in the form of benzylated derivatives, in the form of carbamates, especially of allyl, benzyl, phenyl or tertbutyl, or else in the form of silylated derivatives such as tertbutyl dimethyl, trimethyl or triphenyl derivatives.

or diphenyl tert-butyl silyl.

Deprotection is carried out, according to the nature of the protective group, by sodium or lithium in liquid ammonia, by hydrogenolysis or with the aid of soluble complexes of Palladium O, by action of an acid, or by the action of fluoride. of tetrabutylammonium.

The protection of alcohols is carried out conventionally in the form of ethers, esters or carbonates. The ethers may be alkyl or alkoxyalkyl ethers, preferably methyl or methoxyethoxymethyl ethers, aryl or preferably aralkyl ethers, for example benzyl, or silylated ethers, for example derivatives thereof. silylated above. The esters may be any cleavable ester known to those skilled in the art and preferably acetate, propionate or benzoate or p-nitrobenzoate. The carbonates may be, for example, methyl, tert-butyl, allyl, benzyl or p-nitrobenzyl carbonates.

The deprotection is carried out by the means known to those skilled in the art, in particular saponification, hydrogenolysis, cleavage by soluble complexes of palladium O, hydrolysis in acidic medium or, for silylated derivatives, treatment with tetrabutylammonium fluoride.

The amidification reaction is carried out starting from the carboxylic acid using an activating agent such as an alkyl chloroformate or EDCI, by the action of ammonia or an appropriate amine or their acid salts.

The acylation and sulfonylation reactions are carried out on the hydroxyureas by the action respectively of a suitable halide or carboxylic acid anhydride or a suitable sulfonic acid halide.

The alkylation reaction is carried out by action on the hydroxylated derivatives of an alkyl or substituted alkyl halide, in particular with a free or esterified carboxy radical.

The optional final introduction of a double bond is carried out by the action of a halogenated derivative of selenium and then oxidation, according to methods known to those skilled in the art.

The formation of a urea group is preferably carried out by the action of a suitable isocyanate on the free NH.

The reduction of acids to alcohols can be carried out by the action of a borane or via an intermediate mixed anhydride by the action of an alkaline borohydride. The mixed anhydride is prepared, for example, using an alkyl chloroformate.

The dehydration of amide nitrile can occur under the conditions of the carbonylation and cyclization reactions.

Salification with acids is optionally carried out by adding an acid in the soluble phase to the compound. Salification with bases may concern either compounds having an acid function, especially carboxy, or those containing a sulfooxy function or those comprising an acidic heterocycle. In the first case, one operates by adding a suitable base such as those mentioned above. In the second case, the pyridinium salt is obtained directly during the action of the SO ₃ -pyridine complex and the other salts are obtained from this pyridinium salt. In one or the other case, it is still possible to operate by ion exchange on resin. Examples of salification are given below in the experimental section.

The separation of enantiomers and diastereoisomers can be carried out according to the techniques known to those skilled in the art, in particular chromatography.

The last step of the process according to the invention can, if necessary, be followed by hydrogenolysis so as to convert the R ₁ group to a hydrogen atom.

Illustrations of such reactions defined above are given in the preparation of the examples described hereinafter.

The products of formula (I) as defined above and their addition salts with acids have interesting pharmacological properties.

The products of the present invention can thus be endowed with inhibitory properties of one or more metabolic enzymes as defined above. including kinases or proteases.

Certain products of formula (I) of the present invention as defined above, may therefore in particular have inhibitory properties of certain protein kinases or proteases.

As protein kinases of interest, it is possible to target cathepsins B, H, J, L, N, S, T, C, V W, K or O, O2; especially those involved in diseases of cartilage and bone metabolism and bone cancers, particularly cathepsin K.

The levels, regulation and activity of a number of protein kinases or proteases play a role in several human pathologies. The activity of a protein kinase or protease may notably be associated with receptors possessing transmembrane domains or with intracellular proteins.

Some kinases or proteases may play a role in the initiation, development, and completion of cell cycle events, and thus inhibitory molecules of such kinases or proteases may limit unwanted cell proliferations such as those observed in the cell cycle. cancers, psoriasis, growth of fungi, parasites (animals, protists): such inhibitory molecules of these kinases or proteases are also likely to be involved in the regulation of neurodegenerative diseases such as Alzheimer's disease.

Certain products of formula (I) of the present invention can thus be endowed with antimitotic properties.

Certain products of formula (I) as defined above can as inhibitors of kinase or protease have the particular property of inhibiting bone resorption mediated by osteoclasts. They may therefore be useful for the therapeutic or prophylactic treatment of diseases that are caused at least in part by an unwanted increase in bone resorption, for example osteoporosis.

Certain products of formula (I) of the present invention can thus for example inhibit the adhesion of osteoclasts on the bone surface and thus bone resorption by osteoclasts.

The diseases of the bone whose treatment or prevention require the use of the compounds of formula (I), are in particular osteoporosis, hypercalcemia, osteopenia, for example caused by bone metastases, dental disorders by Examples include periodontitis, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, osteopenia induced by immobilization. In addition, the compounds of formula (I) can be used to relieve, prevent or treat bone disorders caused by treatments, by glucocorticoids, steroid or corticosteroid-related therapies or by deficiencies. of male or female sex hormones.

All these disorders are characterized by bone loss, which is based on a lack of balance between bone formation and bone destruction and which can be favorably influenced by the inhibition of bone resorption by osteoclasts.

Certain products of formula (I) of the present invention may possess in addition to their properties inhibitors specific kinases or proteases, interesting cellular effects such as antiproliferative properties and in particular effects on apoptosis.

It is known from studies described in the literature such as in WO 97/20842 that relationships exist between the cell cycle and apoptosis. Of the pathways leading to apoptosis, some are dependent on kinases or proteases.

The products of the present invention are especially useful for tumor therapy.

The products of the invention can also increase the therapeutic effects of commonly used anti-tumor agents.

The products of formula (I) of the present invention also have antimitotic and anti-neurodegenerative properties.

Certain products of the present invention may be inhibitors of vasoconstrictor and hypertensive effects and thus produce an anti-ischemic effect, or may oppose stimulatory effects on certain cell types, in particular smooth muscle cells, fibroblasts, cells neuronal and bone cells.

The products according to the present invention can thus be used in the treatment of diseases such as proliferative diseases, cancer, restenosis, inflammation; allergies, cardiovascular diseases or certain infectious diseases.

The products of the present invention can also be used in the treatment of certain gastrointestinal, gynecological and especially for a relaxing effect at the level of the uterus.

The products of formula (I) of the present application can thus have interesting pharmacological properties justifying their therapeutic application.

The subject of the invention is therefore also the compounds according to the invention for their use as medicaments, intended for the prevention or treatment of the diseases mentioned above.

The invention particularly relates to pharmaceutical compositions containing as active ingredient at least one of the compounds according to the invention in combination with a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention as defined above may be administered orally, parenterally or locally by topical application to the skin and mucous membranes or by intravenous or intramuscular injection.

These compositions may be solid or liquid and may be in any of the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, pills, lozenges, capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods. The active ingredient can be incorporated into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

The usual dosage, variable according to the product used, the subject treated and the condition in question, may be, for example, from 0.05 to 5 g per day in the adult, or preferably from 0.1 to 2 g. per day.

The subject of the invention is also the use of the compounds according to the invention for the manufacture of medicaments intended for the prevention or treatment of the diseases mentioned above.

The products of the following examples are characterized by their NMR spectra (300 Hz in CDCl ₃ or DMSO) and by their molecular mass MM (positive mode electrospray, results in the form of the mass of the molecular ion H + or in the form of adduct of sodium).

The starting materials of formula (II) are known or can be prepared according to methods known to those skilled in the art. References of literature as well as preparations are possibly provided hereafter in the experimental part.

The following examples illustrate the invention without, however, limiting its scope.

Examples

• M: masse molaire moléculaire
• SM: spectrométrie de masse
• EDCI:1-(3-diméthylamino-propyl)-3-éthylcarbo-diimide chlorhydrate
• AcOEt : acétate d'éthyle
• DMF : N,N-diméthylformamide
• HOBt : 1-hydroxybenzotriazole hydrate
• DMSO : diméthylsulfoxyde

In the following examples the following abbreviations have been used:

• M: molecular molar mass
• MS: mass spectrometry
• EDCI: 1- (3-dimethylamino-propyl) -3-ethylcarbo-diimide hydrochloride
• AcOEt: ethyl acetate
• DMF: N, N-dimethylformamide
• HOBt: 1-hydroxybenzotriazole hydrates
• DMSO: dimethylsulfoxide

Example 1 Synthesis of an acid R ₂ OH

10.69 g (0.12 mM) of β-alanine are dissolved in 60 ml of 2N NaOH (0.12 mM). 17.6 μl (0.132 mmol) of benzyl-methanoic acid chloride and 66 ml (0.132 mmol) of 2N NaOH are added dropwise.

The mixture is kept stirring for 1 h 30 at 0 ° C. The reaction medium is extracted twice with 25 ml of diethyl ether and then brought to pH = 3 with 65 ml of a 2N HCl solution. The precipitate formed is filtered off and dried. 23.4 g of a white solid corresponding to 3 - [(phenylacetyl) amino] propanoic acid are recovered.

The corresponding yield is 94.2%.

NMR spectrum of the proton

In DMSO, at 300 MHz, peak chemical shifts in ppm and multiplicity:
2.5 (t, 2H _a ); 3.35 (q, 2H _b ); 3.5 (s, 1H _c ); 7.3 to 7.5 (m, 5H); 8, 25 (t, 1H)

Example 2 Synthesis of an intermediate acid Step A

291 mg (1.4 mM) of the acid obtained in Example 1 are dissolved in 5 ml of dichloromethane and 0.5 ml of DMF, 368 ml (4.21 mM) of chloride are added dropwise. oxalyl.

After stirring for 3 h at room temperature, the acid chloride is formed and used as such for the rest of the synthesis.

390 mg (1.4 mM) of pyridazine derivative dissolved in 5 ml of dichloromethane and 733 ml of DMF are added to the preceding solution, said pyridazine derivative corresponding to (3S) 1,3-tetrahydro (2H) -pyridazinedicarboxylate. 1- (phenylmethyl) -3-methyl. This compound is obtained by esterification of the corresponding pyridazine-3-carboxylic acid (see also the description as an intermediate in WO-A-9955724, WO-A-9722619 and EP-A-25941).

The reaction medium is stirred at room temperature for 12 hours.

This is concentrated and purified by flash chromatography with a mixture of ethyl acetate / dichloromethane: 80/20. 150 mg of the expected product are recovered, corresponding to (3S) 2- [1-oxo-3 - [(phenylacetyl) amino] propyl] -1-hexahydro-1,3 (2H) -pyridazinedicarboxylate of 1- (phenylmethyl) -3- methyl.

The corresponding yield is 26%.

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity
1.46 and 2.04 (m, 2H _e); 1.72 and 2.1 (m, 2H _d ), 2.61 (m, 2H _b ); 2.90 m, 4.04 and 4.14 (bd, 2H _f), 3.47 (m, _2H's); 3.48 (m, 2H _h ); 3.54 (sl, 3H); 4.73 to 4.98 (m, 1H _g ); 5, 18 (sl, 1H _c ); 5.22 (sl, 1H _g), and 5.96 6, 07 (d, 1H); 7 to 7.4 (m, 10H).

Step B

38 mg (0.08 mM) of the ester obtained in step A are dissolved in 2 ml of methanol. 8.3 μl (0.16 mM) of a 2N sodium hydroxide solution are added. left in contact for 4 hours at room temperature. The reaction medium is concentrated, extracted with 25 ml of ethyl acetate and then acidified with a 1N HCl solution to pH = 1 and then extracted with 25 ml of a solution of ethyl acetate. The organic solution is dried and concentrated to give 31 mg of an oil corresponding to the desired carboxylic acid derivative.
The corresponding yield is 84%.

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.46 and 1.75 (m, 2H _e ); 1.67 and 2.31 (m, 2H _d ), 2.47 (m, 2H _b ); 2.90 m, 4.04 and 4.14 (bd, 2H _f), 3.47 (m, _2H's); 3.48 (m, 2H _h ); 4.73 to 4.98 (m, 1H _g ); 5.18 (sl, 1H _c ); 5.22 (sl, 1H _g), and 5.96 6, 07 (d, 1H); 7 to 7.4 (m, 10H).

Example 3 Synthesis of an HR-amino nitrile ₃

9.59 g (29.8 mM) of a 70% solution in 3-phenoxybenzaldehyde cyanohydrin ether are dissolved in 60 ml of ethanol in a 100 ml metal bomb in the presence of 10 g of MgSO ₄ .

Ammonia gas is bubbled for 1 h while maintaining the medium at -10 ° C and this mixture is stirred at room temperature for 18 h. The mixture is then filtered and evaporated to dryness.
The residue is taken up in 50 ml of an aqueous solution pH = 1, extracted with 50 ml of ethyl acetate. The aqueous phase is then neutralized with Na ₂ CO ₃ and then extracted twice with 50 ml of ethyl acetate. To this solution is added 100 ml of a 20% solution of HCl / AcOEt. The final solution is concentrated to give 3.12 g of a beige powder corresponding to 3-phenoxy α-amino-benzenacetonitrile.
The corresponding yield is 40%.

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
4.88 (sl, 1H); 7.0 (s, 1H _d ); 7.02 (dd, 2H _g ); 7.14 (bt, 1H _e); 7.19 (1H, H _a ); 7.26 (dl, 1H _b ); 7.36 (m, 2H, _f ); 7.37 (m, 1H).

Example 4

31 mg of the acid obtained in Example 2 are dissolved in 1 ml of DMF. To the medium brought to 0 ° C. (ice-salt bath), 14 mg (0.1 mM) of HOBT (1-hydroxybenzotriazole) followed by 20 mg (0.1 mM) of EDCI are added. The mixture brought back to ambient temperature is stored for 1 hour with stirring. 15.3 mg (0.068 mM) of the amine obtained in Example 3 in solution in 2 ml of DMF and 36 μl (0.2 mM) of DIPEA (diisopropylethylamine) are then added to the reaction medium. The mixture is kept at ambient temperature for 12 hours and then poured into 25 ml of water. The solution is extracted with 25 ml of AcOEt, dried and concentrated. The residue obtained is purified by flash chromatography. 22 mg of the expected product are recovered, corresponding to (3S) 2- [1-oxo-3 - [(phenylacetyl) amino] propyl] -3 - [[[cyano (3-phenoxyphenyl) methyl] amino] carbonyl] -tetrahydro -1 (2H) -pyridazinecarboxylate of (phenylmethyl).
The corresponding yield is 50%.

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.46 to 1.75 (m, 2H _e); 1.67 and 2.31 (m, 2H _d ); 2.47 (m, 2H _b ); 2.9 (m, 1H, _f ); 3.47 (m, 2H _a ); 3.48 (m, 2H _h ); 4.04 and 4.14 (dl, 1H _f ); 4.73, 4.98 and 5.22 (m, 2H _g ); 5.18 (sl, 1H _c ); 6.07 (m, 1H); 5.96 and 6.03 (d, 1H _i ); 6.07 (m, 1H); 6.9 to 7.47 (m, 19H _Ar ); 8.42 and 8.5 (dl, 1H).

Example 5

19 mg (0.029 mM) of the 50/50 mixture obtained in Example 4 are dissolved in 2 ml of ethanol. 10 mg of 10% Pd / C is added to this solution. Stirring is maintained for 15 hours at room temperature. The reaction medium is filtered and then concentrated. The residue obtained is purified by flash chromatography to give 10 mg of the expected product which is a 50/50 mixture of 2 diastereoisomers (S, S) and (S, R), corresponding to (3S) 2- [3 - [(phenylacetyl) ) amino] -1-oxopropyl] -N- [cyano (3-phenoxyphenyl) methyl] hexahydro-3-Pyridazinecarboxamide. The corresponding yield is 67%.

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
(mixture of 2 diastereoisomers 50/50): 1.58 (m, 2H _e); 1.70 and 2.37 (m, 2H _d ); 2.33 and 2.94 (m, 2H _b); 2.68, 2.72, 2.91 and 3.01 (m, 2H _f ); 3.27 and 3.37 (m, 1H _h ); 3.52 (sl, 1H _h ); 3.83 (sl), 3.96 (sl) and 3.16 (dl, 2H _a ); 5.14 (ss, 1H _c ); 5.89 and 5.97 (sl, 1H); 6.09 and 6.18 (d, 1H _i ); 8.24 and 8.49 (dl, 1H).

Example 6

From the mixture obtained in Example 4, the two pure diastereoisomers are separated, which are then separately hydrogenated under the same conditions as in Example 5.
There are thus obtained two pure separated diastereoisomers (whose formula is of course the same as that given in Example 5).

Example 7

The procedure is as in Example 4, except that instead of using the amine obtained in Example 3, 3-phenoxybenzaldehyde cyanohydrin (the starting material used to prepare this amine) is used directly. There is thus obtained a mixture of diastereoisomers, corresponding to (3S) 2- [1-oxo-3 - [(phenylacetyl) amino] propyl] -tetrahydro-1,3 (2H) -Pyridazinedicarboxylate of 1- (phenylmethyl) 3- [ (R) cyano (3-phenoxyphenyl) methyl].

NMR spectrum of the proton

In DMSO, at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.49 and 1.79 (m, 2H); 1.80 and 1.90 (m, 2H); 2.30 and 2.54 (m, 2H); 3.01 and 4.09 (m, 2H); 3.36 (sl, 2H); 3.27 (m, 2H); 4.89 and 5.11 (m, 1H); 4.98 and 5.15 (m, 1H); 5.31 (sl, 1H); 6.49 and 6.59 (s, 1H); 6.90 to 7.50 (m, 19H).

Example 8

The compound obtained in Example 7 is deprotected by hydrogenation as indicated in Example 5. This gives a mixture of two diastereoisomers corresponding to (3S) 2- [1-oxo-3 - [(phenylacetyl) amino] propyl] 3- [cyano (3-phenoxyphenyl) methyl] -3-tetrahydro-1,3 (2H) -pyridazinecarboxylate.

Example 9

The procedure is as indicated in Example 4, except that instead of using the amine obtained in Example 3, commercial 3- (p-bromophenoxy) benzaldehyde cyanohydrin is used.
There is thus obtained a mixture of two 50/50 diastereoisomers corresponding to 1- (1-phenylmethyl) (3S) 2- [1-oxo-3 - [(phenylacetyl) amino] propyl] -tetrahydro-1,3 (2H) -pyridazinedicarboxylate 3- [cyano-3 - [(4-bromophenoxy) phenyl] methyl].

NMR spectrum of the proton

In DMSO, at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.51 and 1.78 (m, 2H _e ); 1.76 and 1.97 (m, 2H _d ); 2.24 and 2.54 (m, 2H _b ); 3.22 (m, 2H _b ); 3.35 (m, 2H _h ); 4.03 (m, 2H _f); 5.12 (sl, 1H _g ); 5.18 (sl, 1H _g ); 5.36 (m, 1H _c ); 6.61 (m, 1H _i ); 7.01 to 7.57 (m, 18H _Ar ).
MS (negative electrospray) m / z: [M] ^- = 737

Example 10

The procedure is as in Example 4, except that instead of using the amine obtained in Example 3, commercial (cyanoamino methyl) benzene is used.
A compound corresponding to (3S) 3 - [[(cyanophenylmethyl) amino] carbonyl] -2- [1-oxo-3 - [(phenyl acetyl) amino] propyl] -tetrahydro-1 (2H) -pyridazine carboxylate is thus obtained. of (phenylmethyl).
MS (positive electrospray ) m / z: [MH] ⁺ = 568.3 [MNa] ⁺ = 590.2

Example 11

The compound obtained in Example 10 is deprotected by hydrogenation as indicated in Example 5.
The compound corresponding to (3S) N- (cyanophenylmethyl) -2- [1-oxo-3 - [(phenylacetyl) amino] propyl] hexahydro-3-pyridazinecarboxamide is obtained.

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.58 (m, 2H); 1.71 (m, 1H); 2.35 (m, 1H); 2.28 and 2.98 (m, 1H); 2.38 and 2.87 (m, 1H); 2.70 and 2.97 (m, 2H); 3.16 and 3.92 (m, 1H); 3.19 and 3.77 (m, 1H); 3.54 (sl, 2H); 5.14 (sl, 1H); 5.89 and 6.02 (sl, 2H); 6.09 and 6.21 (dl, 1H); 7.12 to 7.56 (m, 10H); 8.09 and 8.44 (dl, 1H).

Example 12

The procedure is as indicated in Example 4, except that instead of using the amine obtained in Example 3, commercial cyanoamino amine is used.
A compound corresponding to (3S) 2- [1-oxo-3 - [(phenylacetyl) amino] propyl] -3 - [[(cyanoamino)) is thus obtained. phenylmethyl carbonyl] -tetrahydro-1 (2H) -pyridazinecarboxylate.
MS (positive electrospray ) m / z: [MH] ⁺ = 492.3 [MNa] ⁺ = 514.3

Example 13

The compound obtained in Example 10 is deprotected by hydrogenation as indicated in Example 5.
The compound corresponding to (3S) N-cyano-2- [1-oxo-3 - [(phenylacetyl) amino] propyl] hexahydro-3-pyridazine carboxamide is obtained.

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.56 (m, 2H); 1.66 and 2.46 (m, 2H); 2.26 and 3.10 (m, 2H); 2.72 and 2.99 (m, 2H); 3.20 and 4.08 (m, 2H); 3.55 (sl, 2H); 3.78 and 4.09 (dd, 2H); 5.12 (dl, 1H); 6.04 (m, 1H); 7.19 to 7.40 (m, 5H); 7.97 (tl, 1H)

Example 14 Step A

The procedure is as indicated in step A of Example 2, except that instead of using the acid R ₂ OH obtained in Example 1, 3-phenylpropanoic acid is used. There is thus obtained a compound corresponding to (3S) 3-acetyl-2- (3-phenyl-1-oxo-propyl) -tetrahydro-1 (2H) -pyridazine carboxylate (phenylmethyl).

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.46 and 2.04 (m, 2H); 1.72 and 2.04 (m, 2H); 2.60 and 4.21 (m, 2H); 2.61 and 2.91 = (m, 4H); 3.54 (sl, 3H); 5.05 and 5.25 (d, 2H); 5.41 (dl, 1H); 7.10 to 7.33 (m, 10H)

Step B

The product obtained in step A is saponified as indicated in step B of example 2 to obtain an acid.

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.5 (m, 2H); 1.90 (m, 2H); 2.6 (m, 2H); 3.0 (m, 2H); 4.1 (m, 1H); 5.3 (m, 2H); 7.35 (m, 5H); 7.4 (m, 5H).

Step C

Coupling is performed as in Example 4.
A compound corresponding to (3S) 3 - [[[cyano (3-phenoxyphenyl) methyl] amino] carbonyl] -2- [3-phenyl-1-oxo-propyl] -tetrahydro-1 (2H) -pyridazine is thus obtained. (phenylmethyl) carboxylate.
MS (positive electrospray ) m / z: [MH] ⁺ = 740.7

Example 15

The compound obtained in Example 14 is deprotected by hydrogenation as indicated in Example 5.
Two (3S) N- [cyano (3-phenoxyphenyl) methyl] -2- (1-oxo-3-phenylpropyl) -hexahydro-3-pyridazinecarboxamide diastereoisomers are thus obtained.

NMR spectrum of the proton of one of the diastereoisomers

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.52 and 1.71 (m, 2H); 1.77 and 2.09 (m, 2H); 2.62 and 3.02 (m, 2H); 2.87 and 2.90 (m, 4H); 5.18 (sl, 1H); 6.03 (sl, 1H); 6.93 to 7.43 (m, 14H).

Proton NMR spectrum of the other diastereoisomers

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.51 and 1.75 (m, 2H); 1.78 and 2.06 (m, 2H); 2.57 and 2.98 (m, 2H); 2.74 and 2.79 (m, 4H); 5.27 (sl, 1H); 5.96 (sl, 1H); 6.91 to 7.38 (m, 14H).

Example 16 Step A

1 g (3.6 mmol) of the pyrazine derivative used in Example 2 are dissolved in 20 ml of dichloromethane. 0.439 g (3.6 mmol) of DIPEA and 0.616 g (3.6 mMoles) of 3-bromopropanoic acid chloride are added to the solution. The mixture is kept at ambient temperature for 12 hours while stirring. The reaction medium is concentrated to dryness, taken up in 25 ml of ethyl acetate and washed with 25 ml of a 1N HCl solution. The organic phase is dried. The oil obtained is purified by flash chromatography. 1.1 g of the expected product corresponding to (3S) 2- (3-bromo-1-oxo-propyl) -tetrahydro-1,3 (2H) -pyridazinedicarboxylate of 1- (phenylmethyl) -3-methyl are obtained.
The corresponding yield is 75%.

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.99 and 2.07 (m, 2H); 1.83 and 2.09 (m, 2H), 2.94 (m, 2H); 3.48 and 3.61 (m, 2H); 3.03 and 4.33 (m, 2H); 3.56 (s, 3H), 5.09 and 5.27 (m, 2H); 5.40 (dd, 1H); 7.39 (m, 5H)

Step B

0.2 g (0.48 mmol) of the compound obtained in the preceding step is dissolved in 2 ml of DMF. 0.421 mg (4.8 mmol) of morpholine is added to the solution. The mixture is kept for 16 hours with stirring. The medium is poured into 25 ml of water and then extracted with 25 ml of ethyl acetate.
The organic phase is dried and concentrated. The residue obtained is purified by flash chromatography. 91 mg of the expected product are obtained.
The corresponding yield is 50%.

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.53 and 1.92 (m, 2H); 1.78 and 1.92 (m, 2H); 2.3 to 2.7 (m, 4H); 3.52 (s, 3H); 3.38 (m, 4H); 3.57 (m, 4H); 5.18 (m, 1H); 5.04 and 5.2 (m, 2H); 7.35 (m, 4H).

Step C

The product obtained in stage B is saponified as indicated in stage B of example 2.

NMR spectrum of the proton

In DMSO, at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.43 (m, 2H); 1.30 and 1.97 (m, 2H); 2.16 (m, 4H); 2.82 and 4.07 (m, 2H); 3.43 (m, 4H); 4.40 (M, 4H); 4.66 (d, 1H); 4.85 and 5.16 (d 2H); 7.30 (m, 5H).

Step D

The procedure is as in Example 4, except that instead of using the amine obtained in Example 3, commercial (cyanoamino methyl) benzene is used. There is thus obtained a 50/50 mixture of two diastereoisomers corresponding to (3S) 3 - [[(cyanophenylmethyl) amino] carbonyl] -2- (4-morpholinyl carbonyl) -tetrahydro-1 (2H) -pyridazinedicarboxylate (phenylmethyl).

NMR spectrum of the proton

In DMSO, at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.5 (m, 2H); 1.81 (m, 2H); 2.52 (m, 2H); 2.28 (m, 2H); 3.17 and 4.09 (m, 2H); 3.49 (m, 2H); 5.05 and 5.21 (m, 2H); 6.07 (m, 1H); 6.97 to 8.87 (m, 14H); 8.87 (s, 1H).

Example 17

The procedure is as in Example 16, replacing, in step B, the 3-bromopropanoic acid chloride with the acid chloride of 4-morpholine and in step D, the (cyanoamino methyl ) commercial benzene with the amine obtained in Example 3.
The compound corresponding to phenylmethyl (3S) 3 - [[[cyano (3-phenoxyphenyl) methyl] amino] -2 - [(4-morpholinyl) carbonyl] -] tetrahydro-1 (2H) -pyridazinecarboxylate is thus obtained. ).

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.53 and 1.70 (m, 2H); 1.80 and 1.93 (m, 2H); 3.12 and 3.24 (m, 4H); 3.40 (m, 4H); 4.34 (s, 1H); 5.05 and 5.17 (m, 2H); 6.10 (sl, 1H); 6.98 to 7.49 (m, 14H)

Example 18

The compound obtained in Example 17 is deprotected by hydrogenation as indicated in Example 5.
A compound corresponding to (3S) N- [cyano (3-phenoxyphenyl) methyl] -2 - [(4-morpholinyl) carbonyl] hexahydro-3-pyridazinecarboxamide is thus obtained.

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.57 and 1.76 (m, 2H); 1.83 and 2.14 (m, 2H); 2.77 and 2.98 (m, 2H); 3.31 and 3.48 (m, 4H); 3.62 (m, 4H); 4.52 (m, 1H); 6.09 (m, 1H); 6.95 to 7.4 (m, 9H)

Example 19

The procedure is as in Example 16, replacing, in step B, the 3-bromopropanoic acid chloride with the acid chloride of 4-morpholine.
There is thus obtained a compound corresponding to (3S) 3 - [[(cyanophenylmethyl) amino] carbonyl] -2- (4-morpholinyl carbonyl) -tetrahydro-1 (2H) -pyridazinedicarboxylate (phenylmethyl).

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.60 and 1.75 (m, 2H); 1.85 and 2.35 (m, 2H); 3.64 and 3.50 (m, 4H); 3.29 and 3.43 (m, 4H); 3.36 and 3.96 (m, 1H); 3.38 and 4.07 (m, 1H); 4.66 and 4.92 (m, 1H); 5.23 and 5.27 (m, 1H); 6.04 (m, 1H); 7.4 (m, 10H).

Example 20

The compound obtained in Example 19 is deprotected by hydrogenation as indicated in Example 5.

There is thus obtained a compound corresponding to (3S) N- [cyanophenylmethyl] -2 - [(4-morpholinyl) carbonyl] hexahydro-3-pyridazinecarboxamide.

NMR spectrum of the proton

In CDCl ₃ , at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.83 to 3.30 (m, 6H); 3.35 (m, 4H); 3.67 (m, 4H); 4.7 (m, 1H); 6.14 (m, 1H); 7.4 (m, 5H)

Example 21

The procedure is as in Example 16, replacing, in step B, the 3-bromopropanoic acid chloride with the acid chloride of 4-morpholine and in step D, the (cyanoamino methyl ) commercial benzene with cyanoamino methane.
A compound corresponding to (3S) 3 - [[[cyano (3-phenoxyphenyl) methyl] amino] -2 - [(4-morpholinyl) carbonyl] -] - tetrahydro-1 (2H) -pyridazine carboxylate is thus obtained ( phenylmethyl).
MS (positive electrospray) m / z: [MH] ⁺ = 415

Example 22

The procedure is as in Example 16, replacing, in step B, the 3-bromopropanoic acid chloride with the acid chloride of 4-morpholine and in step D, the (cyanoamino methyl ) commercial benzene with 1-cyano 1-amino cyclohexane.
There is thus obtained a compound corresponding to (3S) 3 - [[(1-cyanocyclohexyl) amino] carbonyl] -2 - [(4-morpholinyl) carbonyl] -tetrahydro-1 (2H) -pyridazinecarboxylate (phenylmethyl).

NMR spectrum of the proton

In DMSO, at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.20 to 2.15 (m, 12H); 1.76 and 2.02 (m, 2H); 3.17 and 3.33 (m, 4H); 3.51 (m, 4H); 3.50 and 3.92 (m, 2H); 4.33 (sl, 1H); 5.0 to 5.25 (m, 2H); 7.36 (m, 5H)

Example 23

The compound obtained in Example 22 is deprotected by hydrogenation as indicated in Example 5.
A compound corresponding to (3S) N- (1-cyanocyclohexyl) -2 - [(4-morpholinyl) carbonyl] hexahydro-3-pyridazinecarboxamide is thus obtained.

NMR spectrum of the proton

In CDCL3, at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.32 to 1.62 (m, 2H); 1.47 to 1.62 (m, 2H); 1.62 to 1.97 (m, 2H); 1.67 (m, 2H); 1.72 to 2.31 (m, 3H); 1.83-2.24 (m, 2H); 1.83-2.24 (m, 2H); 2.92 to 3.14 (m, 2H); 3.43 to 3.56 (m, 4H); 3.70 (m, 4H); 4.56 (sl, 1H);

Example 24 Step A

The compound obtained in step A of Example 16 is deprotected as described in Example 5 to obtain the compound corresponding to (3S) 2 - [(4-morpholinyl) carbonyl] -tetrahydro-1 (2H) - pyridazinecarboxylate methyl.

Step B

To a solution of 5 ml of DMF containing 100 mg (0.002 mol) of NaH, 200 mg (0.8 mmol) of ester dissolved in 5 ml of DMF are introduced dropwise. at 0 ° C. After When the mixture is returned to ambient temperature, 320 ml (5 mmol) of methyl iodide are added. The reaction medium is kept at 150 ° C. with stirring. The medium is poured into 25 ml of water and then extracted with 25 ml of ethyl acetate, the organic phase is dried and concentrated. After purification by flash chromatography, 125 mg of an oil corresponding to methyl (3S) 2 - [(4-morpholinyl) carbonyl] -1-methyl-tetrahydro-1 (2H) -pyridazinecarboxylate are obtained.
The corresponding yield is 60%.

NMR spectrum of the proton

In DMSO, at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.38, 1.76 and 1.84 (ss, 4H); 2.50 (m, 3H); 2.81 and 2.91 (m, 2H); 3.33 (m, 4H); 3.53 (m, 4H); 3.56 (s, 3H); 4.04 (sl, 1H)

Step C

The product obtained in step B is saponified as indicated in Step B of Example 2.

NMR spectrum of the proton

In DMSO, at 300 MHz, peak chemical shifts in ppm and multiplicity:
1.51 and 1.61 (m, 1H); 1.83 (m, 2H); 2.53 (s, 3H); 2.86 (m, 2H); 3.36 (m, 4H); 3.55 (m, 4H); 4.02 (t, 1H)

Step D

The procedure is carried out with the product obtained in step C as indicated in Step D of Example 16, replacing the commercial (cyanoamino methyl) benzene with the amine obtained in Example 3.

The product corresponding to (3S) N- [cyano (3-phenoxyphenyl) methyl] -1-methyl-2 - [(4-morpholinyl) carbonyl] hexahydro-3-pyridazinecarboxamide is thus obtained.
MS (positive electrospray) m / z: [MH] ⁺ = 464

Example 25 Step A

This step is identical to that of example 24.

Step B

To a solution of 3 ml of DMF containing 200 mg (0.8 mmol) of ester is added 400 mg of potassium carbonate (2.72 mmol). The mixture is heated to 100 ° C. 322 ml (2.4 mmol) of benzyl bromide are introduced. The mixture is kept stirring for 15 hours at 100 ° C. The medium is poured into 25 ml of water and then extracted with 25 ml of ethyl acetate. The organic phase is dried and concentrated. After purification by flash chromatography, 158 mg of an oil corresponding to methyl (3S) 2 - [(4-morpholinyl) carbonyl] -1-phenylmethyl-tetrahydro-1 (2H) -pyridazinecarboxylate are recovered.
The corresponding yield is 59%.
MS (positive electrospray) m / z: [MH] +: 348

Step C:

The product obtained in stage C is saponified as indicated in stage B of example 2 and the corresponding carboxylic acid is obtained.
The corresponding yield is 91%.
MS (positive electrospray) m / z: [MH] +: 334

Step D:

The procedure is carried out with the product obtained in stage C as indicated in stage D of example 16, replacing the commercial (cyanoamino methyl) benzene with the amine obtained in example 3.
The product (mixture of 2 diastereoisomers) corresponding to (3S) N- [cyano (3-phenoxyphenyl) methyl] -1- (phenylmethyl) -2 - [(4-morpholinyl) carbonyl] hexahydro-3-pyridazinecarboxamide is thus obtained. . The 2 diastereoisomers are separated by flash chromatography.
28 mg of iso A and 16.5 mg of iso B are obtained (overall yield = 27%).

NMR spectrum of the proton

• Premier Isomère : 1.63 à 1.77 (m, 2H) ; 1.94 (m, 2H) ; 2.78 (m, 2H) ; 3.29 (m, 4H) ; 3.51 (t, 4H) ; 3.84 (m, 1H) ; 3.91 (m, 2H) ; 3.99(m, 1H) ; 4.20 (m, 1H) ; 6.08 et 6.16 (d, 1H) ; 6.98 à 7.42 (m, 14H) ; 8.91 et 9.00 (sl,1H).
• Deuxième isomère : 1.62 à 1.77 (m, 2H) ; 1.94 (m, 2H) ; 2.78 (m, 2H) ; 3.30 (m, 4H) ; 3.51 (m, 4H) ; 3.84 (m, 1H) ; 3.92 (m, 2H) ; 4.01 (m, 1H) ; 4.20 (m, 1H) ; 6.08 et 6.16 (d, 2H) ; 6.98 à 7.42 (m, 14H) ; 8.91 et 9.00 (sl,1H).

In DMSO, at 300 Mhz, chemical shifts of the peaks in PPM and multiplicity:

• First isomer: 1.63 to 1.77 (m, 2H); 1.94 (m, 2H); 2.78 (m, 2H); 3.29 (m, 4H); 3.51 (t, 4H); 3.84 (m, 1H); 3.91 (m, 2H); 3.99 (m, 1H); 4.20 (m, 1H); 6.08 and 6.16 (d, 1H); 6.98 to 7.42 (m, 14H); 8.91 and 9.00 (sl, 1H).
• Second isomer : 1.62 to 1.77 (m, 2H); 1.94 (m, 2H); 2.78 (m, 2H); 3.30 (m, 4H); 3.51 (m, 4H); 3.84 (m, 1H); 3.92 (m, 2H); 4.01 (m, 1H); 4.20 (m, 1H); 6.08 and 6.16 (d, 2H); 6.98 to 7.42 (m, 14H); 8.91 and 9.00 (sl, 1H).

Example 26 Pharmacological study of the products of the invention Inhibition study of Cathepsin K

The products to be tested (10 mM) are diluted to 1 mM DMSO and distributed in Nunc polystyrene 96 well plates at a rate of 2 μl per well. The column 12 of the plate is reserved for the controls and thus receives 1 .mu.l of DMSO (without products) per well. The plates are stored at -80 ° C and thawed on the day of the experiment.
The products are diluted to 50 μM by addition of 38 μl of reaction buffer: 100 mM sodium acetate, 5 mM EDTA, 1 mM DTT, pH 5.5. The addition as well as all subsequent pipetting are performed by a pipettor 96 CybiWell cones. After mixing the solutions, each product is transferred to 2 wells (duplicates) of a 384 well black Greiner plate at 10 μl per well. It is therefore possible to test 2 plates 96 in a plate 384.
A 50 μM substrate solution, Z-Val-arg-AMC (Calbiochem), is prepared in the reaction buffer. The substrate is then distributed in all the wells of the 384 plate (20 .mu.l per well).
Catechin K solution at 12.5 ng / ml is prepared in the reaction buffer and distributed in all the wells of the 384 plate (20 .mu.l per well) except for the 16 wells serving as 100% inhibition controls (column 23 and 24, lines I to P) which will receive 20 .mu.l of buffer without enzyme. The 100% inhibition controls are performed in columns 23 and 24, lines A to H which do not contain products.
The plates are then incubated for 2 hours at room temperature, then read on Fluoroskan (Labsystems):
390 nm excitation; 460 nm emission

The final concentrations of each of the reagents are:
10 μM Products, 20 μM Substrate, 5 ng / ml Enzyme.
% Inhibition for each of the products is calculated using 0 points and 100% inhibition of each plate as references. The products exhibiting a significant inhibition are then retested over a concentration range ranging from 50 to 0.5 μM to determine an IC 50.

Results

The IC50s found for certain products are given in Table I below, in micromoles: <b> TABLE I </ b> Example IC ₅₀ (μM) 4 1-10 5.6 <1 7 1-10 8 1-10 9 1-10 10 1-10 11 1-10 12 1-10 13 1-10 14 1-10 15 <1 (2 values)

Example 25 Pharmaceutical composition

Tablets having the following formula were prepared: Composed of Example 1 500 mg Excipient for a tablet finished at 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).

Claims (24)

1. Products of formula (I):

   

   in which:

   R₁ represents a hydrogen atom or a linear or branched alkyl group containing from 1 to 6 carbon atoms, COR or COOR, R being chosen from the group consisting of a linear or branched alkyl radical containing from 1 to 6 carbon atoms, optionally substituted with a pyridyl or carbamoyl radical, a linear or branched -CH₂-alkenyl radical containing in total from 3 to 9 carbon atoms, an aryl radical containing from 6 to 10 carbon atoms or an aralkyl radical containing from 7 to 11 carbon atoms, the nucleus of the aryl or aralkyl radical being optionally substituted with an OH radical, NH₂ radical, NO₂ radical, linear or branched alkyl radical containing from 1 to 6 carbon atoms or linear or branched alkoxy radical containing from 1 to 6 carbon atoms, or with 1 to 3 halogen atoms,

   R₂ represents a group corresponding to formula (II) below:

   

   in which
   n is 0, 1, 2 or 3; a double bond possibly being present when n is 2 or 3;
   X is one of the following groups:

   saturated or unsaturated monocyclic or bicyclic heterocyclic group; or

   an aryl group containing from 6 to 10 carbon atoms or an aralkyl group containing from 7 to 11 carbon atoms, the nucleus of the aryl or aralkyl radical being optionally substituted with an OH radical, NH₂ radical, NO₂ radical, linear or branched alkyl radical containing from 1 to 6 carbon atoms or linear or branched alkoxy radical containing from 1 to 6 carbon atoms, or with 1 to 3 halogen atoms; or a group NR₄R₅, R₄ being a linear or branched alkyl group containing from 1 to 6 carbon atoms or a group COR, CONHR, CSNHR or SO₂R, R having the meaning given above and R₅ being a hydrogen atom or a linear or branched alkyl radical containing from 1 to 6 carbon atoms; or

   a group COR, R having the meaning given above

   R₃ is group of formula -Y-(CH₂)_m-C(CN)R₆R₇, in which:

   Y is an oxygen atom or a group -N(R₈)-,

   R₈ being a hydrogen atom or a linear or branched alkyl group containing from 1 to 6 carbon atoms,

   m is 0, 1, 2 or 3,

   R₆ is a hydrogen atom, a linear or branched alkyl group containing from 1 to 6 carbon atoms or an alkyl or aralkyl group, the nucleus of the aryl or aralkyl radical being optionally substituted with an OH radical, NH₂ radical, NO₂ radical, linear or branched alkyl radical containing from 1 to 6 carbon atoms, linear or branched alkoxy radical containing from 1 to 6 carbon atoms, or aryloxy radical of 7 to 11 carbon atoms, this aryloxy group being itself optionally substituted with 1 to 3 halogen atoms,

   R₇ is a hydrogen atom or a linear or branched alkyl group containing from 1 to 6 carbon atoms,

   or R₆ and R₇ together possibly forming a saturated 6-membered ring;

   said products of formula (I) being in any possible racemic, enantiomeric or diastereoisomeric isomer form; and also the addition salts of these products with mineral and organic acids or with mineral and organic bases.
2. Compound according to Claim 1, characterized in that R₁ is a hydrogen atom or a methyl, benzyl, -COO-benzyl or -CO-methylenebenzyl group.
3. Compound according to Claim 1 or Claim 2, characterized in that n is equal to 0 or 2.
4. Compound according to one of Claims 1 to 3, characterized in that X is an NR₄R₅ group and R₅ is a hydrogen atom.
5. Compound according to one of Claims 1 to 3, characterized in that X is a phenyl or -NHCO-benzyl group.
6. Compound according to one of Claims 1 to 3, characterized in that X is a group

   
7. Compound according to one of Claims 1 to 6, characterized in that R₈ is a hydrogen atom.
8. Compound according to one of Claims 1 to 7, characterized in that R₇ is a hydrogen atom.
9. Compound according to one of Claims 1 to 8, characterized in that R₆ is a hydrogen atom.
10. Compound according to one of Claims 1 to 8, characterized in that R₆ is a phenyl, -C₆H₄-O-C₆H₅ or -C₂H₄-O-C₆H₄Br group.
11. Compound according to one of Claims 1 to 10, characterized in that m is equal to 0 or 2.
12. Compound according to Claim 1, chosen from the following compounds:

    (3S)-2-[3-[(phenylacetyl)amino]-1-oxopropyl]-N-[cyano-(3-phenoxyphenyl)methyl]hexahydro-3-pyridazine-carboxamide, and

    (3S)-N-[cyano(3-phenoxyphenyl)methyl]-2-[1-oxo-3-phenylpropyl)hexahydro-3-pyridazinecarboxamide.
13. Compound according to any one of Claims 1 to 12, having the following stereochemistry:

    
14. Compound according to one of claims 1 to 13, for its use as a medicinal product.
15. Compound according to Claim 14, for its use as a medicinal product for preventing or treating diseases in which metabolic enzymes chosen from proteases and kinases are involved.
16. Compound according to Claim 14 or 15, for its use as a medicinal product for preventing or treating diseases in which cathepsin K is involved.
17. Compound according to Claim 15 or 16, the diseases to be prevented or treated being chosen from the group of diseases consisting of cardiovascular diseases, cancers, diseases of the central nervous system, inflammatory diseases, infectious diseases and bone diseases.
18. Compound according to Claim 15 or 16, the diseases to be prevented or treated being osteoporosis, hypercalcaemia, osteopenia, gingival diseases, arthritis, Paget's disease and bone cancers.
19. Pharmaceutical composition containing, as active principle, at least one compound according to one of Claims 1 to 18, in combination with a pharmaceutically acceptable support.
20. Use of a compound according to one of Claims 1 to 18, for the preparation of a medicinal product for preventing or treating diseases in which metabolic enzymes chosen from proteases and kinases are involved.
21. Process for preparing a product according to one of Claims 1 to 13, characterized in that it includes the step of reaction of a product of formula (IV)

    

    in which R₁ and R₂ have the same meaning as in one of Claims 1 to 13,
    with an aminonitrile or cyanohydrin of formula HR₃, in which R₃ has the same meaning as in one of Claims 1 to 13, to obtain a product of formula (I).
22. Process for preparing a product according to one of Claims 1 to 13, characterized in that it includes:

    1) a step during which a product of formula (II)

    

    is reacted with an acid chloride of formula R₂Cl, in which R₁ and R₂ have the same meanings as in one of Claims 1 to 13 and R' is a linear or branched alkyl group containing from 1 to 6 carbon atoms, to obtain the product of formula (III):

    

    2) a step during which the product of formula (III) obtained in step 1) is hydrolysed to the product of formula (IV):

    

    3) a step during which the product of formula (IV) obtained in step 2) is reacted with an aminonitrile or cyanohydrin of formula HR₃, in which R₃ has the same meaning as in one of claims 1 to 13, to obtain a product of formula (I).
23. Process according to Claim 21 or 22, characterized in that it includes a step of hydrogenolysis of the final product.
24. Process according to one of Claims 21 to 23,
    characterized in that it includes one or more of the following optional reactions, in an appropriate order:

    - protection of reactive functions;

    - deprotection of reactive functions;

    - esterification;

    - saponification;

    - amidation;

    - acylation;

    - sulfonylation;

    - alkylation;

    - introduction of a double bond;

    - formation of a urea group;

    - reduction of carboxylic acids;

    - dehydration of amide to nitrile;

    - salification;

    - ion exchange;

    - resolution or separation of diastereoisomers.